Over 60% of people treated with clozapine continue to have persistent symptoms and cognitive impairments and little data is available to support evidence-based recommendations to guide clinicians in treating these patients. Recent data suggests that adjunct treatment with minocycline may offer symptom improvement in patients with schizophrenia who are taking clozapine. Minocycline has novel and interesting molecular effects, including AMPA receptor modulation and anti-inflammatory and neuroprotective effects, which suggest it may have a significant role in treatment of neurologic and psychiatric disorders. Minocycline is currently available generically; its side effects are well-described and minimal. The proposed 10-week double-blind randomized treatment study seeks to demonstrate that adjunctive minocycline offers patients superior efficacy for persistent positive symptoms, cognitive impairments, and/or other components of schizophrenia pathology. This knowledge could lead to the more effective treatment of patients with schizophrenia. This novel research itself may lead to a better understanding of the pathophysiology of positive symptoms and cognitive impairments, which could contribute to improved treatments in the future. In addition we will examine the effects of minocycline on inflammatory cytokines and the mediating effects these may have in symptom improvement. PUBLIC HEALTH RELEVANCE: Little evidence is available to guide treatment in people with schizophrenia with persistent symptoms despite clozapine treatment. Preliminary data suggests that minocycline may be effective in clozapine treated patients, possibly through its modulation of the glutamate (AMPA) system and its effects on inflammatory cytokines. This study examines adjunct minocycline vs. placebo in a double blind randomized trial for people with schizophrenia who have persistent symptoms on clozapine. We will examine changes in symptomatology, neurocognitive functioning, inflammatory cytokines, and patient satisfaction/wellbeing.